Process for preparation of dicarboxylic acid monoesters

ABSTRACT

A process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and a metal alkoxide to transesterification in the presence of an organic solvent, or a process for producing a dicarboxylic acid monoester which comprises subjecting a dicarboxylic acid monoester or an alkali metal salt of a dicarboxylic acid monoester and an alcohol to transesterification in the presence of a metal alkoxide.

TECHNICAL FIELD

The present invention relates to a process for producing dicarboxylicacid monoesters by transesterification of a dicarboxylic acid monoesterwhich are useful as intermediates for medicines and agriculturalchemicals, main starting materials for polyester polyols, nylons,fibers, lubricants, plasticizers, etc., or additives thereto orprecursors thereof, especially useful as starting materials forsynthesis of asymmetrical diesters of dicarboxylic acids.

BACKGROUND ART

Transesterifications using catalysts containing tin, titanium, etc. arewell known, but these catalysts are deactivated if acids are present inthe reaction systems. Therefore, these catalysts cannot be used forsubstrates containing carboxylic acid in the structure, such asdicarboxylic acid monoesters.

Under the circumstances, many processes for the production ofdicarboxylic acid monoesters have been proposed, and these are roughlyclassified into the following five processes.

(a) Monoesterification of dicarboxylic acids:

Fiziol. Akt. Veshchestva, 7, 129-31(1975).

J. Chem. Res. Synopses, (5), 119(1977). JP-A-4-112854

(b) Decomposition of dicarboxylic acid diesters:

Tetrahedron Lett., 32(34), 4239-42(1991).

Chem. Lett., (7), 539-40(1995).

(c) Ring opening of cyclic dicarboxylic acid anhydrides with alcohols ormetal alkoxides:

Synlet, 6, 650-2(1995).

(d) Condensation reaction:

J. Org. Chem., 33(2), 838-40(1968).

Tetrahedron Lett., (32), 2721-3(1974).

J. Organomet. Chem., 364(3), C29-32(1989).

(e) Synthesis of malonic monoesters from Meldrum's acid:

Tetrahedron Lett., 30(23), 3073-6(1989).

However, these processes (a)-(e) all have the following problems.

In the process (a), both the two carboxyl groups are esterified toproduce diesters as by-products, and in the process (b), both the estergroups are hydrolyzed to produce dicarboxylic acids as by-products.Therefore, according to these processes, it is difficult to obtainmonoesters with a high selectivity, and thus it is difficult toindustrially efficiently obtain the desired monoesters. In the process(c), the reaction is carried out under a high pressure and specialpressure reaction vessels such as autoclave are needed, resulting inincrease of production cost. Moreover, according to this process, twokinds of monoesters are produced at the same time, and, hence, it isdifficult to obtain selectively a monoester with a carboxyl group of thedesired position being monoesterified. Furthermore, according to thisprocess, when optically active monoesters are obtained using opticallyactive cyclic dicarboxylic acid anhydrides as a starting material, thereis the possibility that optical purity of the monoesters greatlydecreases. In the case of the processes (d) and (e), the kinds ofdicarboxylic acid monoesters which can be synthesized are limited and itis difficult to apply these processes to the production of a widevariety of dicarboxylic acid monoesters.

For these reasons, a process for industrially producing a wide varietyof dicarboxylic acid monoesters at a high selectivity has been desired.Moreover, a process for producing dicarboxylic acid monoesters usingoptically active starting materials without causing a great reduction inoptical purity has also been desired.

In general, transesterification between esters and metal alkoxides isknown. However, when a dicarboxylic acid monoester as a startingmaterial for esters and a metal alkoxide are subjected totransesterification in an organic solvent, production of a metal salt ofthe dicarboxylic acid monoester takes place in preference totransesterification, and since the resulting metal salt is hardlysoluble in the organic solvent, it is considered that the desiredtransesterification hardly proceeds. There is no report on actuallyperforming such reaction.

DISCLOSURE OF INVENTION

The present inventors have found that contrary to the above conventionalcommon knowledge, even if a metal salt of dicarboxylic acid monoesterrepresented by the formula (1) is produced in the reaction system, thetransesterification satisfactorily proceeds by selecting the reactionconditions.

The object of the present invention is to provide a process forproducing dicarboxylic acid monoesters according to which a wide varietyof dicarboxylic acid monoesters can be obtained at a high selectivity bysubstituting a desired alkoxy group for an alkoxy group of the estermoiety of dicarboxylic acid monoesters which can be synthesized by knownprocesses, and, furthermore, and optically active dicarboxylic acidmonoesters can be produced from optically active starting materials withless deterioration of optical purity.

As a result of an intensive research conducted by the present inventorsin an attempt to attain the above object, it has been found that a widevariety of dicarboxylic acid monoesters can be obtained at a highselectivity by subjecting an alcohol and a dicarboxylic acid monoesteror an alkali salt of a dicarboxylic acid monoester totransesterification in the presence of a metal alkoxide or by subjectinga metal alkoxide and a dicarboxylic acid monoester or an alkali metalsalt of a dicarboxylic acid monoester to transesterification in thepresence of an organic solvent. Thus, the present invention has beenaccomplished.

That is, the present invention relates to a process for producing adicarboxylic acid monoester represented by the formula (3) whichcomprises subjecting a dicarboxylic acid monoester or an alkali metalsalt of a dicarboxylic acid monoester represented by the formula (1) asa starting material and a metal alkoxide represented by the formula (2)to transesterification in the presence of an organic solvent:

R¹OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (1)

wherein R¹ represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom, m and n each represent aninteger of 0-12 (m+n≦18), X represents a group represented by one of theformula (X1) to the formula (X5), and M¹ represents a hydrogen atom oran alkali metal,

in which Z¹ and Z² each represent a hydrogen atom, a fluorine atom, aphenyl group, a naphthyl group or a straight-chain or branched-chainalkyl group or alkenyl group of 1-12 carbon atoms,

in which Z³, Z⁴, Z⁵ and Z⁶ each represent a hydrogen atom, a fluorineatom, a chlorine atom or a bromine atom,

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1);

R²OM²  (2)

wherein R² represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom, and M² represents analkali metal]; and

R²OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (3)

wherein R² is as defined in the formula (2), and m, n, X and M¹ are asdefined in the formula (1).

Furthermore, the present invention relates to a process for producing adicarboxylic acid monoester represented by the formula (5) whichcomprises subjecting a dicarboxylic acid monoester or an alkali metalsalt of a dicarboxylic acid monoester represented by the formula (1) asa starting material and an alcohol represented by the formula (4) totransesterification in the presence of a metal alkoxide represented bythe above formula (2):

R³OH  (4)

wherein R³ represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom; and

R³OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (5)

wherein R³ is as defined in the formula (4), and m, n, X and M¹ are asdefined in the formula (1)

BEST MODE FOR CARRYING OUT THE INVENTION

The dicarboxylic acid monoesters or alkali metal salts of thedicarboxylic acid monoesters used as a starting material in the presentinvention are not limited as far as they are represented by the formula(1), and they may be those which are commercially available orsynthesized by known processes. As these dicarboxylic acid monoesters oralkali metal salts of the dicarboxylic acid monoesters (hereinafterreferred to as “starting monoesters”), mention may be made of, forexample, monoesters of adipic acid, terephthalic acid, malonic acid,methylsuccinic acid, succinic acid, itaconic acid, citraconic acid,glutaric acid and the like, or metal salts of these monoesters. Themetals which form the metal salts here are not limited as far as theyare alkali metals, but potassium and sodium are preferred, and potassiumis especially preferred because the salts formed are superior insolubility. Moreover, the starting monoesters may be optical activecompounds.

The metal alkoxides used as a starting material of thetransesterification in place of alcohol are not limited as far as theyare represented by the formula (2), but potassium alkoxides areespecially preferred because they are superior in solubility. The kindof the alkoxy group of the metal alkoxides depends on the desireddicarboxylic acid monoesters and is not particularly limited. Preferredare methoxy group, ethoxy group, n-propoxy group, n-butoxy group andtert-butoxy group. When the metal alkoxide is used as a startingmaterial of the transesterification, the amount of the metal alkoxidemay be 1.01 mol or more per mol of the starting dicarboxylic acidmonoester (hereinafter sometimes referred to as “starting monoester”),and preferably 1.01-3 mols per mol of the starting mono-esters takingthe cost into consideration. If the amount of the metal alkoxide is lessthan 1 mol per mol of the starting monoesters, an acid-base reactiontakes place preferentially and this is not preferred.

The metal alkoxides to be allowed to exist in the reaction system whenalcohol is used as a starting material of the transesterification inplace of metal alkoxide are not limited as far as they are representedby the formula (2), but potassium alkoxides are especially preferredbecause they are superior in solubility. The kind of the alkoxy group ofthe metal alkoxides is not limited, but preferred are methoxy group,ethoxy group, n-propoxy group, n-butoxy group and tert-butoxy group.However, if the alkoxy group of the starting alcohol is different fromthat of the metal alkoxide, undesired esters are partially produced,and, hence, it is preferred to use a metal alkoxide having the samealkoxy group as of the alcohol represented by the formula (4) used inthe reaction. When the metal alkoxide is used as a catalyst for thetransesterification as mentioned above, the amount of the metal alkoxidemay be 1.01 mol or more per mol of the starting monoester in the case ofthe starting monoesters being dicarboxylic acid monoester, andpreferably 1.01-3 mols per mol of the starting monoester taking the costinto consideration. In the case of the starting monoesters being thealkali metal salt, the amount of the metal alkoxide may be 0.01 mol ormore per mol of the starting monoester, and preferably 0.01-2 mols permol of the starting monoester taking the cost into consideration.

The alcohols used as a starting material in the present invention arenot limited as far as they are represented by the formula (4). Examplesof these alcohols (hereinafter referred to as “starting alcohols”)include straight-chain aliphatic alcohols such as methanol, ethanol,n-propyl alcohol and n-butyl alcohol, branched aliphatic alcohols suchas isopropyl alcohol, isobutyl alcohol and tert-butyl alcohol,unsaturated aliphatic alcohols such as allyl alcohol and methallylalcohol, alcohols containing aromatic group such as benzyl alcohol,4-nitrobenzyl alcohol, 3,5-dinitrobenzyl alcohol and phenethyl alcohol,and cellosolve alcohols such as ethylene glycol monomethyl ether anddiethylene glycol monomethyl ether.

The amount of the starting alcohol used is preferably 1-200 mols,especially preferably 5-50 mols per mol of the starting monoesters. Whenthe starting monoesters are an alkali metal salt, it is preferred to usethe starting alcohol in a greatly excess amount over the amount of thealkali metal salt of the starting monoester for the purposes ofimproving the solubility of the alkali metal salt as the startingmonoester, shortening the reaction time and improving the conversion inthe transesterification. However, in case the starting alcohol has ahigh boiling point and is difficult to remove by distillation aftercompletion of the reaction or the amount of the starting alcohol shouldbe decreased because of its high price, use of the starting alcohol in aslightly excess amount per mol of the starting monoesters can fullyattain the purposes.

When an alcohol is used as a starting material and a metal alkoxide isused as a catalyst, the order of mixing of the starting materials beforesubjected to the reaction is not particularly limited, and, for example,there are the following methods: a method of mixing the startingmonoesters with the alcohol which is another starting material andthereafter adding the metal alkoxide (method A); a method of mixing thestarting alcohol with the metal alkoxide and thereafter adding thestarting monoesters (method B); a method of mixing the startingmonoesters with the metal alkoxide and thereafter adding the startingalcohol (method C); a method of mixing the starting monoesters with anorganic solvent and an additive and thereafter adding the metal alkoxide(method D); a method of mixing the metal alkoxide with an organicsolvent and an additive and thereafter adding the starting monoesters(method E); etc. The order of mixing according to methods A, B, D and Eare preferred from the point of operability.

When the starting monoesters are optical active compounds having anasymmetric center at α-position, there is the possibility of α-hydrogenof the is ester being drawn by the metal alkoxide. Therefore, in orderto maintain a high optical purity of the product, it is preferred to addthe metal alkoxide lastly as in the method A or D.

When a starting alcohol is used in the present invention, the solventand the additive are not necessarily needed, but they may be used forthe acceleration of the reaction. When the starting alcohol is not used,a solvent is necessarily used and an additives) can be optionally added.

The solvents usable include organic solvents, for example, aromatichydrocarbon solvents such as benzene, nitrobenzene, toluene and xylene,ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane,1,3-dioxolan and 1,4-dioxane, carbon disulfide, nitromethane,N,N-dimethylformamide, and dimethyl sulfoxide.

The additives are preferably those which activate the carbonyl group ofthe metal alkoxide or ester, those which have an effect of increasingthe solubility of the metal alkoxide or the starting monoesters or thosewhich have an effect as a phase-transfer catalyst. Examples of theadditives include amines such as triethylamine andtetramethylenediamine, nitrogen-containing aromatic compounds such aspyridine, quaternary ammonium salts such as benzyltriethylammoniumchloride and tetra-n-butylammonium bromide, crown ethers such as18-crown-6, and compounds having an inclusion effect similar to that ofthe crown ethers, such as tetrahydrofuran, 1,2-dimethoxyethane,1,3-dioxolan and 1,4-dioxane.

Reaction temperature of the transesterification can be optionally setusually in a range of −100 to 250° C., preferably −80 to 200° C., morepreferably −20 to 150° C. Since the reaction of the present invention isan equilibrium reaction, in order to improve the reaction rate and theconversion, it is preferred to carry out the reaction while alcohol(R¹OH) produced from the starting monoesters by transesterification isremoved out of the reaction system by evaporation, etc. Therefore, thereaction temperature is preferably not less than the boiling point orazeotropic point of the alcohol (R¹OH) produced by thetransesterification. In case the alcohol resulting from the metalalkoxide used as a starting material or the starting alcohol is alsosimultaneously distilled off by evaporation, this alcohol or a solutioncontaining this alcohol may be added to the reaction system.

The pressure during the transesterification can be optionally setusually in a range of 1 kPa-5 MPa (absolute pressure). Practically, 10kPa-1 MPa (absolute pressure) is preferred, and 80-120 kPa (absolutepressure) is more preferred. The reaction time of thetransesterification can be optionally set usually in a range of 0.01-100hours, and 0.1-50 hours is preferred considering the efficiency ofreaction vessel.

The present invention will be further specifically explained by thefollowing examples and comparative examples, which should not beconstrued as limiting the present invention in any manner.

The analysis in the examples and comparative examples was conducted bygas chromatography (hereinafter referred to as “GC”), high-performanceliquid chromatography (hereinafter referred to as “HPLC”), and NMR.

The purity of the final products was calculated by the following formulafrom peak area in a GC or HPLC chart.

Purity(%)=A/B×100

wherein A denotes a peak area of the dicarboxylic acid monoester whichis the desired product, and B denotes the total of peak areas of thedesired product and all impurities.

Furthermore, yield was calculated by the following formula.

Yield(%)=C/D×100

wherein C denotes the number of mols of the di-carboxylic acid monoesterwhich is the desired product (calculated by dividing the product of thepurity and the weight of the final product containing impurities by themolecular weight of the dicarboxylic acid monoester which is the desiredproduct), and D denotes the number of mols of the starting monoesters.

EXAMPLE 1 Synthesis of mono-tert-butyl adipate

Ten grams (0.057 mol) of monoethyl adipate and 200 ml (2.081 mols) oftert-butyl alcohol were charged in a glass flask equipped with astirrer, a dropping funnel, a thermometer, an Oldershaw column and aDimroth condenser, and 7.73 g (0.069 mol, 1.2 equivalent) ofpotassium-tert-butoxide was poured thereinto little by little at roomtemperature. As a result, the reaction mixture generated heat to causerising of the temperature to 35° C., and white crystals wereprecipitated in the reaction mixture. Thereafter, the reaction mixturewas heated to 83° C. and the reaction was carried out for 16.5 hours,during which ethyl alcohol produced by the transesterification wasdistilled off together with tert-butyl alcohol, and tert-butyl alcoholin the same amount as the amount of the distilled tert-butyl alcohol wascontinuously added through the dropping funnel. After completion of thetransesterification, tert-butyl alcohol was distilled off under normalpressure, and the residue was allowed to stand for cooling. Then, 80 mlof ice water was added to the residue, followed by separation washingtwice with 100 ml of n-hexane. To the resulting aqueous phase was added3.96 g (0.039 mol, 1.4 equivalent) of sulfuric acid diluted with 20 mlof cold water to liberate the acid. The components in the aqueous phasewere analyzed by GC to obtain a peak area ratio of 20:80 of the startingmonoethyl adipate and the product mono-tert-butyl adipate. This aqueousphase was subjected to extraction twice with 100 ml of n-hexane, andthen the n-hexane phase extracted twice was washed thrice with 10 ml ofpure water and thereafter subjected to concentration under reducedpressure. As a result, 7.20 g of mono-tert-butyl adipate of 92% inpurity containing no monoethyl adipate was obtained. The yield in thiscase was 57%. Spectrum data of ¹H-NMR on the product were as follows.

¹H-NMR(CDCl₃) 1.48 (9H, s), 1.64-1.68 (4H, m), 2.22-2.27 (2H, m),2.33-2.40 (2H, m), 9.64 (1H, br).

EXAMPLE 2 Synthesis of mono-tert-butyl terephthalate

In the same manner as in Example 1, 10 g (0.056 mol) of monomethylterephthalate and 200 ml (2.081 mols) of tert-butyl alcohol werecharged, and 8.10 g (0.070 mol, 1.3 equivalent) ofpotassium-tert-butoxide was poured thereinto little by little at roomtemperature. As a result, the reaction mixture generated heat to resultin rising of the temperature to 35° C., and white crystals wereprecipitated in the reaction mixture. Thereafter, the reaction mixturewas heated to 83° C. and the reaction was carried out for 17 hours,during which methyl alcohol produced by the transesterification wasdistilled off together with tert-butyl alcohol, and tert-butyl alcoholin the same amount as the amount of the distilled tert-butyl alcohol wascontinuously added through the dropping funnel. After completion of thetransesterification, tert-butyl alcohol was distilled off under normalpressure, and the residue was allowed to stand for cooling. Then, 80 mlof ice water was added to the residue, followed by separation washingtwice with 100 ml of n-hexane. To the resulting aqueous phase was added3.85 g (0.036 mol, 1.4 equivalent) of sulfuric acid diluted with 20 mlof cold water to liberate the acid. The components in the aqueous phasewere analyzed by GC to obtain a peak area ratio of 66:34 of the startingmonomethyl terephthalate and the product mono-tert-butyl terephthalate.This aqueous phase was subjected to extraction twice with 100 ml ofn-hexane, and then the n-hexane phase extracted twice was washed thricewith 10 ml of pure water and thereafter subjected to concentration underreduced pressure. As a result, 2.99 g of mono-tert-butyl terephthalateof 94% in purity containing no monomethyl terephthalate was obtained.The yield in this case was 23%. Spectrum data of ¹H-NMR on the productwere as follows.

¹H-NMR(CDCl₃) 1.62 (9H, s), 8.08 (2H, d, J=8.1 Hz), 8.16 (2H, d, J=8.1Hz).

EXAMPLE 3 Synthesis of monoisopropyl malonate

In the same manner as in Example 1, 5 g (0.029 mol) of potassium salt ofmonoethyl malonate and 100 ml (1.305 mol) of isopropyl alcohol werecharged, and 0.41 g (0.0059 mol, 0.2 equivalent) of potassium methoxidewas poured thereinto little by little at room temperature. As a result,the reaction mixture generated heat to result in rising of thetemperature to 35° C., and white crystals were precipitated. Thereafter,the reaction mixture was heated to 82° C. and the reaction was carriedout for 6 hours, during which ethyl alcohol produced by thetransesterification was distilled off together with isopropyl alcohol,and isopropyl alcohol in the same amount as the amount of the distilledisopropyl alcohol was continuously added through the dropping funnel.After completion of the transesterification, isopropyl alcohol wasdistilled off under normal pressure, and the residue was allowed tostand for cooling. Then, 100 ml of ice water was added to the residue,followed by separation washing once with 100 ml of ethyl acetate. To theresulting aqueous phase was added 1N hydrochloric acid to adjust the pHto 2. The components in the aqueous phase was analyzed by HPLC to obtaina peak area ratio of 4:96 of monoethyl malonate resulting from thestarting potassium salt of monoethyl malonate and the productmonoisopropyl malonate. The analysis conditions by HPLC are shown below.

Analysis conditions for high-performance liquid chromatography:

Column: ODS-120A

Mobile phase: Water/acetonitrile/phosphoric acid=20:80:0.1 (vol)

Flow rate: 0.7 ml/min

Detection: 220 nm

This aqueous phase was subjected to extraction twice with 100 ml ofethyl acetate, and then the ethyl acetate phase extracted twice waswashed twice with 100 ml of pure water and thereafter subjected toconcentration under reduced pressure. As a result, 4.03 g ofmonoisopropyl malonate of 95% in purity containing no monoethyl malonatewas obtained. The yield in this case was 90%. Spectrum data of ¹H-NMR onthe product were as follows.

¹H-NMR (CDCl₃) 1.27 (6H, d, J=6.21 Hz), 3.40 (2H, s), 5.08 (1H, se,J=6.21 Hz), 9.53 (1H, br).

EXAMPLE 4 Synthesis of monobenzyl malonate

In the same manner as in Example 1, 10 g (0.059 mol) of potassium saltof monoethyl malonate and 200 ml (1.929 mol) of benzyl alcohol werecharged, and 0.1 g (0.0001 mol, 0.02 equivalent) of potassium methoxidewas poured thereinto little by little at room temperature. As a result,the reaction mixture generated heat to result in rising of thetemperature to 35° C., and white crystals were precipitated. Thereafter,the reaction mixture was heated to 90° C. and the reaction was carriedout for 6 hours, during which ethyl alcohol (containing a slight amountof methyl alcohol resulting from potassium methoxide) produced by thetransesterification was continuously distilled off. After completion ofthe reaction, the reaction mixture was left to stand for cooling. Then,100 ml of ice water was added thereto, followed by subjecting toseparation washing once with 100 ml of ethyl acetate. To the resultingaqueous phase was added 1N hydrochloric acid to adjust the pH to 2. Thecomponents in the aqueous phase was analyzed by HPLC to find thatmonoethyl malonate resulting from the starting potassium salt ofmonoethyl malonate was not detected and only the product monobenzylmalonate was detected. The analysis conditions for HPLC were the same asin Example 3. This aqueous phase was subjected to extraction twice with100 ml of ethyl acetate, and then the ethyl acetate phase extractedtwice was washed twice with 100 ml of pure water and thereaftersubjected to concentration under reduced pressure. As a result, 10.83 gof monobenzyl malonate of 100% in purity was obtained. The yield in thiscase was 95%. Spectrum data of ¹H-NMR on the product were as follows.

¹H-NMR(CDCl₃) 3.41 (2H, s), 5.22 (2H, s), 7.37 (5H, s).

EXAMPLE 5 Synthesis of 4-tert-butyl itaconate

In the same manner as in Example 1, 1.44 g (0.013 mol, 1.2 equivalent)of potassium-tert-butoxide and 15 ml (0.156 mol) of tert-butyl alcoholwere charged, and 1.5 g (0.010 mol) of 4-methyl itaconate was pouredthereinto little by little at room temperature. As a result, thereaction mixture generated heat to result in rising of the temperatureto 35° C., and white crystals were precipitated. Thereafter, thereaction mixture was heated to 83° C. and the reaction was carried outfor 7 hours, during which methyl alcohol produced by thetransesterification was distilled off together with tert-butyl alcohol,and tert-butyl alcohol in the same amount as the amount of the distilledtert-butyl alcohol was continuously added through the dropping funnel.After completion of the transesterification, tert-butyl alcohol wasdistilled off under normal pressure, and the residue was allowed tostand for cooling. Then, 26 ml of ice water was added to the residue,followed by separation washing once with 30 ml of n-hexane. To theresulting aqueous phase was added 0.74 g (0.07 mol, 1.4 equivalent) ofsulfuric acid diluted with 4 ml of cold water to liberate the acid. Thecomponents in the aqueous phase were analyzed by GC to find that thepeak area ratio of the starting 4-methyl itaconate and the product4-tert-butyl itaconate was 61:39. This aqueous phase was subjected toextraction twice with 30 ml of n-hexane, and then the n-hexane phaseextracted twice was washed once with 3 ml of pure water and thereaftersubjected to concentration under reduced pressure. As a result, 0.54 gof 4-tert-butyl itaconate of 88% in purity containing no 4-methylitaconate was obtained. The yield in this case was 24%. Spectrum data of¹H-NMR on the product were as follows.

¹H-NMR(CDCl₃) 1.45 (9H, s), 3.26 (2H, s), 5.78 (1H, s), 6.42 (1H, s),8.05 (1H, br).

EXAMPLE 6 Synthesis of 4-benzyl (R)-methylsuccinate

In the same manner as in Example 1, 4.67 g (0.082 mol, 1.2 equivalent)of potassium methoxide and 150 ml (1.447 mol) of benzyl alcohol werecharged, and 10 g (0.060 mol) of 88% by weight of 4-methyl(R)-methylsuccinate (optical purity: 94%e.e.) was added dropwise theretoover a period of 5 minutes at room temperature. As a result, thereaction mixture generated heat to result in rising of the temperatureto 35° C., and white crystals were precipitated. Thereafter, thereaction mixture was heated to 100° C. and the reaction was carried outfor 5 hours, during which methyl alcohol produced by thetransesterification and a slight amount of methyl alcohol resulting frompotassium methoxide were continuously distilled off. After completion ofthe reaction, the reaction mixture was allowed to stand for cooling.Then, 100 ml of ice water was added thereto, followed by separationwashing once with 100 ml of ethyl acetate. To the resulting aqueousphase was added 4.94 g (0.048 mol, 1.4 equivalent) of sulfuric aciddiluted with 25 ml of cold water to liberate the acid. The components inthe aqueous phase were analyzed by GC to find that the peak area ratioof the starting 4-methyl (R)-methylsuccinate and the product 4-benzyl(R)-methylsuccinate was 17:83. This aqueous phase was subjected toextraction twice with 100 ml of ethyl acetate, and then the ethylacetate phase extracted twice was washed once with 20 ml of pure waterand thereafter subjected to concentration under reduced pressure. As aresult, 7.87 g of 4-benzyl (R)-methylsuccinate of 87% in purity wasobtained. The yield in this case was 51%. The 4-benzyl(R)-methylsuccinate had an optical purity of 94% e.e., and no reductionof optical purity relative to the starting methyl ester was seen. TheSpectrum data of ¹H-NMR on the product were as follows.

¹H-NMR(CDCl₃) 1.25 (3H, d, J=6.8 Hz), 2.42 (2H, dd, J=12.7, 5.9 Hz),2.74 (2H, dd, J=12.7, 8.4 Hz), 2.96 (1H, dtd, J=8.4, 6.8, 5.9 Hz), 5.13(2H, s), 7.35 (5H, s), 10.74 (1H, br).

The optical purity was obtained by analysis using HPLC with convertingthe starting 4-benzyl (R)-methyl-succinate to (R)-methylsuccinic acidwith 2 equivalents of aqueous sodium hydroxide solution. The analysisconditions for HPLC are shown below.

Column: CHIRALCEL OD

Mobile phase: n-hexane/isopropyl

alcohol/trifluoroacetic acid=90:10:0.1(vol)

Flow rate: 0.5 ml/min

Detection: 220 nm

The starting 4-methyl (R)-methylsuccinate was prepared by the processdisclosed in JP-A-8-285.

EXAMPLE 7 Synthesis of 4-tert-butyl (R)-methylsuccinate

142.5 g (1.231 mols, 1.2 equivalent) of potassium-tert-butoxide and 1500ml (5.202 mols) of tert-butyl alcohol were charged in a glass flaskequipped with a stirrer, a dropping funnel, a thermometer, an Oldershawcolumn and a Dimroth condenser, and 150 g (0.904 mol) of 88% by weightof 4-methyl (R)-methylsuccinate (optical purity: 94%e.e.) was addeddropwise thereto at room temperature over a period of 5 minutes. As aresult, the reaction mixture generated heat to result in rising of thetemperature to 35° C., and white crystals were precipitated. Thereafter,the reaction mixture was heated to 83° C. and the reaction was carriedout for 26 hours, during which methyl alcohol produced by thetransesterification was distilled off together with tert-butyl alcohol,and tert-butyl alcohol in the same amount as the amount of the distilledtert-butyl alcohol was continuously added through the dropping funnel.After completion of the transesterification, tert-butyl alcohol wasdistilled off under normal pressure, and the residue was allowed tostand for cooling. Then, 1100 ml of ice water was added to the residue,followed by separation washing once with 1000 ml of n-hexane. To theresulting aqueous phase was added 75.6 g (0.74 mol, 1.4 equivalent) ofsulfuric acid diluted with 400 ml of cold water to liberate the acid.The components in the aqueous phase were analyzed by GC to obtain amolar ratio of 25:75 (75% in terms of conversion) of the starting4-methyl (R)-methylsuccinate and the product 4-tert-butyl(R)-methylsuccinate. This aqueous phase was subjected to extractiontwice with 1500 ml of n-hexane, and then the n-hexane phase extractedtwice was washed thrice with 300 ml of pure water and thereaftersubjected to concentration under reduced pressure. As a result, 100.9 gof 4-tert-butyl (R)-methylsuccinate of 92.0% in purity containing no4-methyl (R)-methylsuccinate was obtained. The yield in this case was58%. The optical purity of 4-tert-butyl (R)-methylsuccinate was 92%e.e.,and reduction of the optical purity relative to the starting methylester was slight. Spectrum data of ¹H-NMR on the product were asfollows.

¹H-NMR(CDCl₃) 1.24 (3H, d, J=6.8 Hz), 1.44 (9H, s), 2.36 (2H, dd,J=16.3, 6.1 Hz), 2.64 (2H, dd, J=16.3, 8.1 Hz), 2.90 (1H, dtd, J=8.1,6.8, 6.1 Hz), 9.73 (1H, br).

The optical purity of the starting 4-methyl (R)-methylsuccinate and thatof the product 4-tert-butyl (R)-methylsuccinate were obtained byanalysis using HPLC with converting them to (R)-methylsuccinic acid with2 equivalents of aqueous sodium hydroxide solution and with a greatlyexcess amount of trifluoroacetic acid, respectively. The analysisconditions for HPLC were the same as in Example 6.

EXAMPLE 8 Synthesis of 4-tert-butyl (R)-methylsuccinate

In the same manner as in Example 7, 10 g (0.066 mol) of 97% by weight of4-methyl (R)-methylsuccinate (optical purity: 99%e.e.) and 100 ml (1.040mols) of tert-butyl alcohol were charged, and 9.5 g (0.082 mol, 1.2equivalent) of potassium-tert-butoxide was added dropwise thereto atroom temperature over a period of 5 minutes. As a result, the reactionmixture generated heat to result in rising of the temperature to 35° C.,and white crystals were precipitated. Thereafter, the reaction mixturewas heated to 83° C. and the reaction was carried out for 15.5 hours,during which methyl alcohol produced by the transesterification was notdistilled off. After completion of the transesterification, the producedmethyl alcohol and tert-butyl alcohol were distilled off under reducedpressure, and the residue was allowed to stand for cooling. Then, 75 mlof ice water was added to the residue, followed by separation washingonce with 100 ml of n-hexane. To the resulting aqueous phase was added4.75 g (0.046 mol, 1.4 equivalent)of sulfuric acid diluted with 25 ml ofcold water to liberate the acid. The components in the aqueous phasewere analyzed by GC to obtain a molar ratio of 65:35 (35% in terms ofconversion) of the starting 4-methyl (R)-methylsuccinate and the product4-tert-butyl (R)-methylsuccinate. This aqueous phase was subjected toextraction twice with 100 ml of n-hexane, and then the n-hexane phaseextracted twice was washed six times with 20 ml of pure water andthereafter subjected to concentration under reduced pressure. As aresult, 3.76 g of 4-tert-butyl (R)-methylsuccinate of 99% in puritycontaining no 4-methyl (R)-methylsuccinate was obtained. The yield inthis case was 30%. The optical purity of 4-tert-butyl(R)-methylsuccinate was 99%e.e., and no reduction of the optical purityrelative to the starting methyl ester was seen. Spectrum data of ¹H-NMRon the product were the same as in Example 7. The optical purity wasmeasured in the same manner as in Example 7.

EXAMPLE 9 Synthesis of 4-tert-butyl (R)-methylsuccinate

In the same manner as in Example 7, 158.3 g (1.369 mol, 2.0 equivalents)of potassium-tert-butoxide and 1000 ml (10.404 mols) of tert-butylalcohol were charged, and 100 g (0.664 mol) of 97% by weight of 4-methyl(R)-methylsuccinate (optical purity: 99%e.e.) was added dropwise theretoat room temperature over a period of 5 minutes. As a result, thereaction mixture generated heat to result in rising of the temperatureto 35° C., and white crystals were precipitated. Thereafter, thereaction mixture was heated to 83° C. and the reaction was carried outfor 30 minutes, during which methyl alcohol produced by thetransesterification was not distilled off. After completion of thetransesterification, methyl alcohol produced and tert-butyl alcohol weredistilled off under reduced pressure, and the residue was allowed tostand for cooling. Then, 1000 ml of ice water was added to the residue,followed by separation washing once with 1000 ml of n-hexane. To theresulting aqueous phase was added 171.3 g (1.643 mols, 1.4 equivalent)of concentrated hydrochloric acid to liberate the acid. The componentsin the aqueous phase were analyzed by GC to obtain a molar ratio of20:80 (80% in terms of conversion) of the starting 4-methyl(R)-methylsuccinate and the product 4-tert-butyl (R)-methylsuccinate.This aqueous phase was subjected to extraction twice with 1000 ml ofn-hexane, and then the n-hexane phase extracted twice was washed thricewith 100 ml of pure water and thereafter subjected to concentrationunder reduced pressure. As a result, 89.54 g of 4-tert-butyl(R)-methylsuccinate of 99% in purity containing no 4-methyl(R)-methylsuccinate was obtained. The yield in this case was 71%. Theoptical purity of 4-tert-butyl (R)-methylsuccinate was 94%e.e., andreduction of the optical purity relative to the starting methyl esterwas slight. Spectrum data of ¹H-NMR on the product were the same as inExample 7. The optical purity was measured in the same manner as inExample 7.

EXAMPLE 10 Synthesis of 4-tert-butyl (R)-methylsuccinate

In the same manner as in Example 7, 103.0 g (1.050 mol, 1.2 equivalent)of sodium tert-butoxide and 1450 ml (15.085 mols) of tert-butyl alcoholwere charged, and 145.2 g (0.875 mol) of 88% by weight of 4-methyl(R)-methylsuccinate (optical purity: 94%e.e.) was added dropwise theretoat room temperature over a period of 5 minutes. As a result, thereaction mixture generated heat to result in rising of the temperatureto 35° C., and white crystals were precipitated in the reaction mixture.Thereafter, the reaction mixture was heated to 83° C. and the reactionwas carried out for 3 hours, during which methyl alcohol produced by thetransesterification was distilled off together with tert-butyl alcohol,and tert-butyl alcohol in the same amount as the distilled tert-butylalcohol was continuously added through the dropping funnel. Aftercompletion of the transesterification, methyl alcohol produced andtert-butyl alcohol were distilled off under reduced pressure, and theresidue was allowed to stand for cooling. Then, 1095 ml of ice water wasadded to the residue, followed by separation washing once with 1000 mlof n-hexane. To the resulting aqueous phase was added 71.0 g (0.695 mol,1.4 equivalents) of sulfuric acid diluted with 355 ml of cold water toliberate the acid. The components in the aqueous phase were analyzed byGC to obtain a molar ratio of 70:30 (30% in terms of conversion) of thestarting 4-methyl (R)-methylsuccinate and the product 4-tert-butyl(R)-methylsuccinate. This aqueous phase was subjected to extractiontwice with 1450 ml of n-hexane, and then the n-hexane phase extractedtwice was washed six times with 290 ml of pure water and thereaftersubjected to concentration under reduced pressure. As a result, 30.8 gof 4-tert-butyl (R)-methylsuccinate of 99% in purity containing no4-methyl (R)-methylsuccinate was obtained. The yield in this case was19%. The optical purity of 4-tert-butyl (R)-methylsuccinate was 94%e.e.,and no reduction of the optical purity than the starting methyl esterwas seen. Spectrum data of ¹H-NMR on the product were the same as inExample 7. The optical purity was measured in the same manner as inExample 7.

EXAMPLE 11 Synthesis of 4-tert-butyl (R)-methylsuccinate

A metal tert-butoxide an additive and a solvent were charged, and4-methyl (R)-methylsuccinate was added dropwise thereto at 0° C. or roomtemperature over a period of 5 minutes. As a result, white crystals wereprecipitated in the reaction mixture. After completion of thetransesterification, 30% cold sulfuric acid (1.4 equivalents) was addedto liberate the acid. This aqueous phase was subjected to extractiontwice with n-hexane, and then the n-hexane phase extracted twice waswashed five times with pure water and thereafter subjected toconcentration under reduced pressure. As a result, 4-tert-butyl(R)-methylsuccinate of higher than 90% in purity containing no 4-methyl(R)-methylsuccinate was obtained. The yield in this case was as shown inTable 1. Spectrum data of ¹H-NMR on the products were the same as inExample 7. The optical purity was measured in the same manner as inExample 7.

TABLE 1 Reaction conditions Optical Amount of solvent purity/% ee t-BuOM(equivalent) (ml/g) based on Temperature (Optical purity Additive(equivalent) reaction scale of bath Reaction time Yield/% of substrate)Reaction scale t-BuOK (3.0) t-BuOH (10) rt 30 min 39.2 97 (98) 20 gt-BuOK (2.2) DMSO (5) rt 16.5 h 4.0 92 (98) 20 g t-BuOK (2.2) dioxane(7.5) rt 30 min 27.8 93 (97) 200 g t-BuOK (2.2) dioxolane (7.5) rt 1 h28.5 95 (97) 200 g t-BuONa (2) DME (20) rt 16 h 39.1 87 (94) 10 gt-BuONa (2.2) DME (7.5) rt 30 min 28.2 93 (97) 200 g t-BuOK (2.2) DME(7.5) rt 30 min 32.0 94 (97) 200 g t-BuONa (2.2) THF (5) 0° C. 2 h 35.786 (94) 20 g t-BuOK (2.2) THF (10) rt 4.5 h 30.9 90 (98) 20 g t-BuOK (3)THF (5) 0° C. 30 min 37.4 96 (98) 20 g t-BuOK (2.2) THF (7.5) rt 30 min29.9 91 (97) 200 g t-BuOK (2.2) THF (7.5) rt 30 min 24.5 96 (97) 200 gDMSO (2.5) t-BuOK (2.2) THF (7.5) rt 30 min 35.8 94 (97) 200 g pyridine(2.3) t-BuOK (2.2) THF (7.5) rt 30 min 33.1 92 (97) 200 g Et₃N (2.3)t-BuOK (2.2) THF (7.5) rt 30 min 25.9 93 (97) 20 g TMEDA (1.2) t-BuOK(2.2) THF (7.5) 0° C. 1 h 37.3 93 (97) 200 g PhCH₂NEt₃.Cl (0.2) t-BuOK(2.2) THF (3.75)-t-BuOH (2.5) 0° C. 1 h 41.2 96 (97) 200 g PhCH₂NEt₃.Cl(0.2) (Note) rt: Room temperature

Comparative Example 1 Synthesis of 4-tert-butyl (R)-methylsuccinate

In the same manner as in Example 9, 2.84 g (0.290 mol, 1.1 equivalents)of sodium tert-butoxide and 30 ml (0.312 mol) of tert-butyl alcohol werecharged, and 3.0 g (0.260 mol) of 99% by weight of (R)-methylsuccinicanhydride (optical purity: 96%e.e. or more) suspended in 30 ml (0.312mol) of tert-butyl alcohol was added dropwise thereto at roomtemperature over a period of 5 minutes. As a result, the reactionmixture generated heat to result in rising of the temperature to 54° C.,and at this temperature, the reaction was carried out for 30 minutes.After completion of the transesterification, tert-butyl alcohol wasdistilled off under reduced pressure, and the residue was allowed tostand for cooling. Then, 200 ml of ice water was added to the residue,followed by separation washing once with 200 ml of ethyl acetate. To theresulting aqueous phase was added 2.93 g (0.290 mol, 1.1 equivalents) ofconcentrated hydrochloric acid to liberate the acid. This aqueous phasewas subjected to extraction thrice with 200 ml of n-hexane, and then then-hexane phase extracted thrice was washed once with 60 ml of pure waterand thereafter subjected to concentration under reduced pressure. As aresult, 2.0 g of a mixture of 4-tert-butyl (R)-methylsuccinate and1-tert-butyl (R)-methylsuccinate containing no 4-methyl(R)-methylsuccinate was obtained. This mixture was analyzed by GC toobtain a molar ratio of position isomers of 4-ester:1-ester=70:30, andwhen these two components were combined, the purity was 99%. The yieldin this case was 40%. The optical purity of 4-tert-butyl(R)-methylsuccinate was 84%e.e., and a great reduction of the opticalpurity relative to the starting methylsuccinic anhydride was seen. Theoptical purity was measured in the same manner as in Example 7,regarding both the 4-ester and the 1-ester as (R)-methylsuccinic acid.

INDUSTRIAL APPLICABILITY

According to the present invention, a wide variety of dicarboxylic acidmonoesters can be obtained at a high selectivity, and especially whenoptically active esters represented by the formula (1) having anasymmetric center at a-position of carboxylic acid are used as startingmaterials, substantially no reduction of optical purity is seen beforeand after the reaction. Therefore, according to the present invention,there are obtained dicarboxylic acid monoesters which are useful asintermediates for medicines and agricultural chemicals, main startingmaterials or additives for polyester polyols, nylons, fibers,lubricants, plasticizers, etc., or precursors thereof, especially usefulas starting materials for synthesis of asymmetrical diesters ofdicarboxylic acids.

What is claimed is:
 1. A process for producing a dicarboxylic acidmonoester represented by the formula (3) which comprises subjecting adicarboxylic acid monoester or an alkali metal salt of a dicarboxylicacid monoester represented by the formula (1) as a starting material anda metal alkoxide represented by the formula (2) to transesterificationin the presence of an organic solvent:R¹OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (1) wherein R¹ represents astraight-chain or branched-chain alkyl group, alkoxyalkyl group oralkylthioalkyl group of 1-18 carbon atoms, of which one or more hydrogenatoms may be substituted with phenyl group, naphthyl group, toluyl groupor fluorine atom, m and n each represent an integer of 0-12 (m+n≦18), Xrepresents a group represented by one of the formula (X1) to the formula(X5), and M¹ represents a hydrogen atom or an alkali metal,

in which Z¹ and Z² each represent a hydrogen atom, a fluorine atom, aphenyl group, a naphthyl group or a straight-chain or branched-chainalkyl group or alkenyl group of 1-12 carbon atoms,

in which Z³, Z⁴, Z⁵ and Z⁶ each represent a hydrogen atom, a fluorineatom, a chlorine atom or a bromine atom,

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1); R²OM²  (2)wherein R² represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom, and M² represents analkali metal; and R²OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (3) wherein R² isas defined in the formula (2), and m, n, X and M¹ are as defined in theformula (1).
 2. A process according to claim 1, wherein thetransesterification is carried out in the presence of a quaternaryammonium salt or a tertiary amine.
 3. A process for producing adicarboxylic acid monoester represented by the formula (5) whichcomprises subjecting an optically active dicarboxylic acid monoester oran alkali metal salt of a dicarboxylic acid monoester represented by theformula (1) as a starting material and an alcohol represented by theformula (4) to transesterification in the presence of a metal alkoxiderepresented by the formula (2): R¹OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (1)wherein R¹ represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom, m and n each represent aninteger of 0-12 (m+n≦18), X represents a group represented by one of theformula (X1) to the formula (X5), and M¹ represents a hydrogen atom oran alkali metal,

in which Z¹ and Z² each represent a hydrogen atom, a fluorine atom, aphenyl group, a naphthyl group or a straight-chain or branched-chainalkyl group or alkenyl group of 1-12 carbon atoms,

in which Z³, Z⁴, Z⁵ and Z⁶ each represent a hydrogen atom, a fluorineatom, a chlorine atom or a bromine atom,

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1),

in which Z¹ and Z² are as defined in the formula (X1); R²OM²  (2)wherein R² represents a straight-chain or branched-chain alkyl group,alkoxyalkyl group or alkylthioalkyl group of 1-18 carbon atoms, of whichone or more hydrogen atoms may be substituted with phenyl group,naphthyl group, toluyl group or fluorine atom, and M² represents analkali metal; R³OH  (4) wherein R³ represents a straight-chain orbranched-chain alkyl group, alkoxyalkyl group or alkylthioalkyl group of1-18 carbon atoms, of which one or more hydrogen atoms may besubstituted with phenyl group, naphthyl group, toluyl group or fluorineatom and R³OOC—(CH₂)_(m)—X—(CH₂)_(n)—COOM¹  (5) wherein R³ is as definedin the formula (4), and m, n, X and M¹ are as defined in the formula(1).
 4. A process according to claim 3, wherein the transesterificationis carried out in the presence of a quaternary ammonium salt or atertiary amine.